Abstract
Aims
There are limited data to support direct oral anticoagulant (DOAC) use in patients with hypertrophic cardiomyopathy (HCM) and non‐valvular atrial fibrillation (NVAF). The current study investigated the safety and effectiveness of DOACs versus warfarin in patients in Japan.
Methods
This retrospective observational study assessed a Japanese cohort of patients diagnosed with HCM and NVAF between July 2011 and June 2021 using a Japanese claims database. Propensity score (PS) matching (2:1 DOAC:warfarin) using the nearest‐neighbour method was applied to balance demographic and clinical characteristics between treatment groups. The primary outcomes were the risk of major bleeding and any bleeding (major or minor). Secondary outcomes included describing baseline demographic and clinical characteristics and the risk of stroke/systemic embolism (SE).
Results
After PS matching, 2955 DOAC‐ and 1603 warfarin‐treated patients were assessed. The mean [standard deviation (SD)] age in the DOAC and warfarin groups was 74.8 (10.5) and 75.3 (10.2) years, respectively. The majority of patients were male (DOAC, 58.8%; warfarin, 59.6%), had comorbidities (DOAC, 97.5%; warfarin, 96.6%), and were treated with β‐blockers (DOAC, 62.5%; warfarin, 62.3%). The risk of major and any bleeding was similar across cohorts [hazard ratio (HR), 0.80; 95% confidence interval (CI), 0.50–1.27; P = 0.336 and HR, 0.93; 95% CI, 0.78–1.11; P = 0.420] while the risk of stroke/SE was lower among patients treated with DOACs (HR, 0.67; 95% CI, 0.47–0.96; P = 0.027). Factors associated with an increased risk of major bleeding included prior bleeding (HR, 1.97; 95% CI, 1.22–3.17) and chronic kidney disease (HR, 1.87; 95% CI, 1.10–3.18). An increased risk of stroke/SE was associated with prior ischaemic stroke (HR, 2.97; 95% CI, 2.05–4.29), peripheral arterial disease (HR, 1.88; 95% CI, 1.22–2.88) and chronic kidney disease (HR, 1.87; 95% CI, 1.24–2.83).
Conclusions
DOAC‐treated patients had a lower risk of stroke/SE and a comparable risk of bleeding compared with warfarin‐treated patients. Prior stroke was shown to augment stroke risk by approximately three‐fold. This large real‐world study suggests that patients diagnosed with HCM and NVAF can be safely and effectively treated with DOACs in Japan.
Keywords: atrial fibrillation, hypertrophic cardiomyopathy, ischaemic stroke, direct oral anticoagulant
Introduction
Hypertrophic cardiomyopathy (HCM) is a complex primary myocardial disorder most commonly characterized by ventricular hypertrophy as well as by a range of heterogeneous morphological, functional and clinical features. 1 , 2 , 3 HCM is one of the most prevalent hereditary cardiomyopathies worldwide and is estimated to affect between 1 in 500 young adults and 1 in 200 adults or greater. 4 , 5 Patients with HCM can be broadly categorized into those with obstructive HCM (oHCM) or non‐obstructive HCM (nHCM) based on the presence or absence of a dynamic left ventricular outflow tract obstruction. 1 , 3
Patients with HCM are often symptomatic and may experience heart failure, ventricular arrhythmias and non‐valvular atrial fibrillation (NVAF). 6 , 7 NVAF has a major impact on clinical outcomes such as heart failure, stroke and mortality 6 , 8 , 9 , 10 and is the most common sustained arrhythmia associated with HCM. Indeed, we recently reported findings of a retrospective observational database study, in which >30% of patients with HCM had comorbid NVAF. 11 In this study, 25%–26% of patients with HCM were treated with direct oral anticoagulants (OACs) (DOACs) or warfarin, accounting for >70% of patients with both HCM and atrial fibrillation (AF). 11
Anticoagulation therapy is recommended to prevent thromboembolism in patients with HCM and AF, unless they have contraindications. 3 Similar to the 2023 European Society of Cardiology (ESC) guideline for cardiomyopathy, 12 the 2018 Japanese Circulation Society (JCS)/Japanese Heart Failure Society (JHFS) guideline 3 recommends oral anticoagulation to reduce the risk of thromboembolic events in patients with HCM with AF (Class I; Level of Evidence B). However, the Japanese guideline states that the use of anticoagulation with warfarin is recommended and that DOACs may be useful based on the results of a single observational study as no randomized controlled trials have been conducted in patients with HCM and AF. 3 On the other hand, in the general AF population, sufficient data have accumulated showing the preference for DOACs over warfarin; consequently, initial anticoagulation with DOACs is recommended in recent arrhythmia guidelines (Class I; Level of Evidence A). 13 , 14 This suggests that DOACs may be used in patients with HCM as well as in the general AF population. 12 In the real world, however, data comparing DOACs with warfarin in patients with AF complicated by HCM are still limited. 15 , 16
Overall, the indication of DOACs or vitamin K antagonists (VKAs) in HCM based on cardiomyopathy guidelines remains unclear due to a lack of randomized data; however, existing data suggest that DOACs and VKAs may be used in a similar manner as in the general population. In other words, data supporting the priority for the use of DOAC and warfarin are still insufficient. To the best of our knowledge, this is the largest study comparing DOACs versus warfarin in patients with HCM and NVAF, complementing the existing literature. 15 , 16
This retrospective observational study aimed to compare the safety and effectiveness clinical outcomes in patients diagnosed with both HCM and NVAF who were treated with DOACs versus those who were treated with warfarin.
Methods
Study design
This retrospective, observational study included patients with HCM and NVAF in a Japanese cohort. Data were extracted from a Japanese hospital‐based administrative claims database provided by Medical Data Vision Co., Ltd. (MDV), Tokyo, Japan, which contained claims data from acute care hospitals using the Diagnosis Procedure Combination (DPC) system. The index treatment date was defined as the patient's first prescription (incident) of an OAC on or after the diagnosis of both HCM and NVAF during the study period (1 July 2011 to 30 June 2021). A 180‐day baseline period was designated before the index date (up to 1 January 2011). Therefore, patient demographic and clinical characteristics were examined between the index date (day 0) and baseline (day −180). Propensity score (PS) matching was applied to the baseline and clinical characteristics.
The follow‐up period was defined as the period from the day following the index date to the date of the first occurrence of any of the following events (whichever occurred first): death of the patient, last activity of the patient in the MDV database, end of the study period, switching from warfarin to DOACs or from DOACs to warfarin, or discontinuation of treatment. Discontinuation was defined as a >45 day gap between taking the same class of treatment. Discontinuation date was calculated using the following formula: [(index date + days of supply) − 1].
Study population
Eligible patients were aged ≥18 years at index treatment initiation and required a diagnosis of both HCM and AF prior to the index date. Patients also required a record of DOAC (apixaban, dabigatran, edoxaban and rivaroxaban) or warfarin treatment following the diagnosis of both HCM and AF. In this study, NVAF was defined as the population of patients with AF from which patients with a diagnosis of valvular AF, rheumatic AF, postoperative AF, previous catheter ablation (CA) procedure, chronic dialysis and venous thromboembolism (VTE) were excluded. In addition, patients with both oHCM and nHCM diagnoses were excluded because we could not distinguish between HCM types [see Table S1 for a list of International Classification of Diseases, 10th Revision (ICD‐10) codes/disease codes/procedure codes]. Exclusion criteria identified during the 180 day baseline period also included a record of treatment with both DOACs and warfarin.
Study outcomes
This study assessed the safety and effectiveness of DOACs compared with warfarin in patients with both HCM and NVAF. The primary outcomes were major bleeding requiring hospitalization and any bleeding (major or minor). The secondary outcomes included a description of baseline demographic and clinical characteristics as well as stroke/systemic embolism (SE) requiring hospitalization. The outcomes were defined as reported in ARISTOTLE according to the International Society of Thrombosis and Haemostasis criteria study 17 , 18 , 19 using ICD‐10 codes.
Major and minor bleeding were identified in the MDV database based on the diagnosis of major or minor bleeding, respectively. Any bleeding was identified in the MDV database based on a diagnosis for bleeding, including both major and minor bleeding. Stroke events identified in the MDV database included ischaemic stroke, haemorrhagic stroke and transient ischaemic attack (TIA). SE events in the MDV database were identified by an SE diagnosis code. Major bleeding and stroke/SE events were also identified at DPC hospitalization. A full list of ICD‐10 diagnosis codes is provided in Table S1.
Ethics statements
This study was conducted in accordance with the International Society for Pharmacoepidemiology Guidelines for Good Pharmacoepidemiology Practices, as well as applicable regulatory requirements. The study required neither review and approval by an ethics committee nor informed consent as the study used de‐identified claims/electronic medical records data.
Statistical analysis
Baseline demographic and clinical characteristics were described according to the exposure group (DOAC‐ and warfarin‐treated patients). Continuous variables were described as mean [standard deviation (SD)], and categorical variables were described as the number and percentage of patients. Patients with no comorbidities were defined as those without the following conditions: diabetes mellitus, hypertension, heart failure (congestive heart failure), chronic kidney disease (CKD), myocardial infarction (MI), peripheral arterial disease (PAD), haemorrhagic stroke, ischaemic stroke/TIA and arrhythmia (except AF). These comorbidities were covariates for PS matching and Cox analysis.
PS matching was performed for the DOAC versus warfarin cohorts. PS was estimated using logistic regression, including the following predictors: age, sex, oHCM/nHCM, individual components of the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/TIA (doubled) (CHADS2) score and comorbidities. Patients were matched 2:1 DOAC to warfarin, without replacement, using the nearest‐neighbour method. A calliper width equal to 0.2 of the SD of the logit of the PS was used. Following matching, the baseline demographic and clinical characteristics were described again to assess PS‐matching success in balancing covariates across the exposure groups. The balance was assessed by comparing the standardized mean differences in covariates between the exposure groups pre‐ and post‐matching. Matched cohorts were assessed for time to event using the Kaplan–Meier method and log‐rank tests. Median time was reported for each outcome, along with the 25th and 75th percentiles and 95% confidence intervals (CIs), when estimable. Only the available data were summarized; no imputation methods were used to handle missing data. Subgroup analyses were performed within matched cohorts and assessed for time‐to‐event using Cox proportional hazards models. Multivariable analysis was performed with the Cox proportional hazard model to investigate risk factors for major bleeding and stroke/SE.
Results
Baseline disposition, demographic and clinical characteristics
During the study period of 1 July 2011 to 30 June 2021, 14216 patients with both NVAF and HCM were assessed for eligibility. After PS matching, 2955 patients remained in the DOAC‐treated group and 1603 patients in the warfarin‐treated group (Figure 1). In the DOAC group, 1114 patients received apixaban (37.7%), 857 received edoxaban (29.0%), 703 received rivaroxaban (23.8%) and 286 received dabigatran (9.7%). The covariate balance after nearest‐neighbour matching for the DOAC and warfarin cohorts is shown in Table S2.
Figure 1.
Flow diagram of the disposition of patients during the study period. AF, atrial fibrillation; CA, catheter ablation; DOAC, direct oral anticoagulant; HCM, hypertrophic cardiomyopathy; nHCM, non‐obstructive HCM; NVAF, non‐valvular AF; oHCM, obstructive HCM; VTE, venous thromboembolism.
Post‐PS matching data are described, and all baseline demographic and clinical characteristics are provided in Table 1. The mean (SD) age of patients in the DOAC and warfarin groups was 74.8 years (10.5) and 75.3 years (10.2), respectively. The proportion of male patients in the DOAC and warfarin groups was 58.8% and 59.6%, respectively. DOAC‐ and warfarin‐treated patients both experienced prior bleeding (20.3% and 22.0%, respectively). Most patients in the DOAC and warfarin groups had comorbidities (97.5% and 96.6%, respectively). DOAC‐ and warfarin‐treated patients experienced hypertension (75.4% and 73.9%, respectively), diabetes mellitus (47.5% and 46.5%, respectively), CKD (12.4% and 19.3%, respectively) and MI (14.8% and 14.6%, respectively). Percutaneous transluminal septal myocardial ablation was not observed in any patient in this study.
Table 1.
Baseline demographic and clinical characteristics.
| Variable | Pre‐PS matching | Post‐PS matching | ||
|---|---|---|---|---|
| DOAC | Warfarin | DOAC | Warfarin | |
| N = 5150 | N = 1604 | N = 2955 | N = 1603 | |
| Age in years, mean (SD) | 73.55 (11.1) | 75.25 (10.2) | 74.83 (10.5) | 75.28 (10.2) |
| Sex, n (%) | ||||
| Male | 3007 (58.4) | 955 (59.5) | 1737 (58.8) | 955 (59.6) |
| Female | 2143 (41.6) | 649 (40.5) | 1218 (41.2) | 648 (40.4) |
| CHADS2 score, mean (SD) | 2.86 (1.2) | 2.93 (1.3) | 2.92 (1.2) | 2.93 (1.3) |
| CHADS2 score, n (%) | ||||
| 0 | 101 (2.0) | 36 (2.2) | 67 (2.3) | 36 (2.3) |
| 1 | 516 (10.0) | 153 (9.5) | 263 (8.9) | 153 (9.5) |
| 2 | 1342 (26.1) | 376 (23.4) | 710 (24.0) | 375 (23.4) |
| 3 | 1808 (35.1) | 578 (36.0) | 1078 (36.5) | 578 (36.1) |
| 4 | 943 (18.3) | 308 (19.2) | 572 (19.4) | 308 (19.2) |
| 5 | 284 (5.5) | 88 (5.5) | 158 (5.4) | 88 (5.5) |
| 6 | 156 (3.0) | 65 (4.1) | 107 (3.6) | 65 (4.1) |
| Prior bleeding, n (%) | 957 (18.6) | 353 (22.0) | 601 (20.3) | 353 (22.0) |
| Comorbidities and procedures, n (%) | ||||
| No comorbidities a | 139 (2.7) | 55 (3.4) | 73 (2.5) | 55 (3.4) |
| Diabetes mellitus | 2693 (52.3) | 746 (46.5) | 1404 (47.5) | 745 (46.5) |
| Hypertension | 3643 (70.7) | 1185 (73.9) | 2228 (75.4) | 1185 (73.9) |
| Heart failure (congestive heart failure) | 4090 (79.4) | 1286 (80.2) | 2391 (80.9) | 1285 (80.2) |
| Dyslipidaemia | 2023 (39.3) | 651 (40.6) | 1171 (39.6) | 651 (40.6) |
| Chronic kidney disease | 369 (7.2) | 309 (19.3) | 366 (12.4) | 309 (19.3) |
| Arrhythmia (except atrial fibrillation) | 1534 (29.8) | 463 (28.9) | 907 (30.7) | 462 (28.8) |
| Myocardial infarction | 968 (18.8) | 235 (14.7) | 438 (14.8) | 234 (14.6) |
| Peripheral arterial disease | 487 (9.5) | 184 (11.5) | 308 (10.4) | 184 (11.5) |
| Haemorrhagic stroke | 133 (2.6) | 38 (2.4) | 66 (2.2) | 38 (2.4) |
| Ischaemic stroke/transient ischaemic attack | 828 (16.1) | 271 (16.9) | 485 (16.4) | 271 (16.9) |
| Malignant tumour | 1037 (20.1) | 321 (20.0) | 615 (20.8) | 321 (20.0) |
| Chronic obstructive pulmonary disease | 360 (7.0) | 167 (10.4) | 224 (7.6) | 167 (10.4) |
| Implantable cardioverter defibrillator | 30 (0.6) | 15 (0.9) | 16 (0.5) | 15 (0.9) |
| HCM subtype, n (%) | ||||
| oHCM | 678 (13.2) | 217 (13.5) | 389 (13.2) | 217 (13.5) |
| nHCM | 4472 (86.8) | 1387 (86.5) | 2566 (86.8) | 1386 (86.5) |
| Medication/treatment, n (%) | ||||
| β‐Blockers | 3168 (61.5) | 1000 (62.3) | 1848 (62.5) | 999 (62.3) |
| Non‐DHP calcium channel blockers | 1007 (19.6) | 286 (17.8) | 573 (19.4) | 285 (17.8) |
| DHP calcium channel blockers | 1167 (22.7) | 425 (26.5) | 714 (24.2) | 425 (26.5) |
| Na channel blockers | 639 (12.4) | 161 (10.0) | 344 (11.6) | 161 (10.0) |
| K channel blockers | 641 (12.4) | 266 (16.6) | 382 (12.9) | 265 (16.5) |
| Angiotensin‐converting enzyme inhibitors | 590 (11.5) | 207 (12.9) | 346 (11.7) | 207 (12.9) |
| Angiotensin II receptor blockers | 1296 (25.2) | 452 (28.2) | 774 (26.2) | 452 (28.2) |
| Diuretics | 1988 (38.6) | 941 (58.7) | 1226 (41.5) | 940 (58.6) |
| Aldosterone antagonists | 952 (18.5) | 418 (26.1) | 582 (19.7) | 417 (26.0) |
| Digitalis | 201 (3.9) | 113 (7.0) | 109 (3.7) | 112 (7.0) |
| Antiplatelets | 717 (13.9) | 313 (19.5) | 447 (15.1) | 313 (19.5) |
Note: Percentages are rounded to one decimal place.
Abbreviations: CHADS2, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or TIA or thromboembolism (doubled); DHP, dihydropyridine; DOAC, direct oral anticoagulant; HCM, hypertrophic cardiomyopathy; nHCM, non‐obstructive HCM; oHCM, obstructive HCM; K, potassium; Na, sodium; PS, propensity score; SD, standard deviation; TIA, transient ischaemic attack.
Defined as patients without the following comorbidities: diabetes mellitus, hypertension, heart failure (congestive heart failure), chronic kidney disease, arrhythmia (except atrial fibrillation), myocardial infarction, peripheral arterial disease, haemorrhagic stroke, or ischaemic stroke/TIA.
β‐Blockers were the most frequently prescribed treatment for both groups (DOAC, 62.5%; warfarin, 62.3%), followed by diuretics (DOAC, 41.5%; warfarin, 58.6%). Patients in the DOAC and warfarin groups received angiotensin‐converting enzyme inhibitors (11.7% and 12.9%, respectively), angiotensin II receptor blockers (26.2% and 28.2%, respectively) and dihydropyridine calcium channel blockers (24.2% and 26.5%, respectively; Table 1). The prescription of warfarin declined from 93.5% to 27.6% of patients during the study period, while prescription of DOACs increased from 11.4% to 82.9% (Figure 2).
Figure 2.
Proportion of patients who received warfarin or DOAC over time. DOAC, direct oral anticoagulant.
Clinical outcomes in the DOAC and warfarin groups
The incidence of major bleeding and any bleeding per 100‐person years was 1.43 and 12.90 in the DOAC group, respectively, compared with 1.71 and 13.20, respectively, in the warfarin group [hazard ratio (HR), 0.80; 95% CI, 0.5–1.27; P = 0.336 and HR, 0.93; 95% CI, 0.78–1.11; P = 0.420, respectively; Table 2 and Figure 3A,C]. The incidence rate per 100 person‐years of stroke/SE was 2.30 and 3.27 in the DOAC and warfarin groups, respectively (HR, 0.67; 95% CI, 0.47–0.96; P = 0.027; Table 2 and Figure 3B).
Table 2.
Safety and effectiveness in the DOAC and warfarin groups
| DOAC (N = 2955) | Warfarin (N = 1603) | Hazard ratio (95% CI) | P value | |||
|---|---|---|---|---|---|---|
| Number of events | Incidence rate per 100 person‐years | Number of events | Incidence rate per 100 person‐years | |||
| Safety outcomes | ||||||
| Major bleeding | 46 | 1.43 | 29 | 1.71 | 0.80 (0.5–1.27) | 0.336 |
| Any bleeding | 353 | 12.90 | 194 | 13.20 | 0.93 (0.78–1.11) | 0.420 |
| Effectiveness | ||||||
| Stroke/SE | 73 | 2.30 | 55 | 3.27 | 0.67 (0.47–0.96) | 0.027 |
Abbreviations: CI, confidence interval; DOAC, direct oral anticoagulant; SE, systemic embolism.
Figure 3.
Kaplan–Meier curves for effectiveness and safety outcomes for time to (A) major bleeding, (B) stroke/SE and (C) any bleeding in the DOAC and warfarin groups. DOAC, direct oral anticoagulant; SE, systemic embolism.
Relative risk of major bleeding and stroke/SE in the DOAC and warfarin groups
Patients with arrhythmia at baseline had a significantly greater reduction in risk of major bleeding when treated with DOACs compared with those treated with warfarin (HR, 0.45; 95% CI, 0.20–0.98; Figure 4A). A significantly greater reduction in risk of stroke/SE was observed when treated with DOACs compared with warfarin among male patients (HR, 0.59; 95% CI, 0.37–0.94) as well as those with the following baseline clinical characteristics: nHCM (HR, 0.64; 95% CI, 0.44–0.92), no prior bleeding (HR, 0.65; 95% CI, 0.43–0.98), hypertension (HR, 0.67; 95% CI, 0.45–0.98), heart failure (HR, 0.61; 95% CI, 0.42–0.90), arrhythmia (HR, 0.55; 95% CI, 0.31–0.99), no MI (HR, 0.64; 95% CI, 0.43–0.93), no PAD (HR, 0.67; 95% CI, 0.45–0.99) and no haemorrhagic stroke (HR, 0.69; 95% CI, 0.48–0.98; Figure 4B).
Figure 4.
(A) Forest plot of the relative risk of major bleeding in the DOAC and warfarin groups. CI, confidence interval; DOAC, direct oral anticoagulant; HCM, hypertrophic cardiomyopathy; nHCM, non‐obstructive HCM; oHCM, obstructive HCM; TIA, transient ischaemic attack. *Value could not be specified because there was no event in the warfarin group in patients without heart failure. (B) Forest plot of the relative risk of stroke/SE in the DOAC and warfarin groups. CI, confidence interval; DOAC, direct oral anticoagulant; HCM, hypertrophic cardiomyopathy; nHCM, non‐obstructive HCM; oHCM, obstructive HCM; TIA, transient ischaemic attack.
Effect of comorbidities and characteristics on the relative risk of major bleeding and stroke/SE
An increased risk of major bleeding was significantly associated with prior bleeding (HR, 1.97; 95% CI, 1.22–3.17) and CKD (HR, 1.87; 95% CI, 1.10–3.18; Figure 5A). An increased risk of stroke/SE was associated with previous ischaemic stroke (HR, 2.97; 95% CI, 2.05–4.29), PAD (HR, 1.88; 95% CI, 1.22–2.88) and CKD (HR, 1.87; 95% CI, 1.24–2.83; Figure 5B).
Figure 5.
(A) Forest plot of the relative risk of major bleeding according to patient baseline characteristics. Haemorrhagic stroke was not included in the analysis owing to the low number of events. CI, confidence interval; DOAC, direct oral anticoagulant; HCM, hypertrophic cardiomyopathy; nHCM, non‐obstructive HCM; TRT, treatment. (B) Forest plot of the relative risk of stroke/SE according to patient baseline characteristics. Haemorrhagic stroke was not included in the analysis owing to the low number of events. CI, confidence interval; DOAC, direct oral anticoagulant; HCM, hypertrophic cardiomyopathy; nHCM, non‐obstructive HCM; oHCM, obstructive HCM; TRT, treatment.
Discussion
This study analysed data for 4558 patients with HCM and NVAF from a large database of DPC hospitals in Japan. We investigated the baseline characteristics and thromboembolic and bleeding events in patients treated with DOACs compared with those treated with warfarin. To the best of our knowledge, this is the largest medical claims database study conducted to date globally, which was conducted in patients with both HCM and NVAF.
The rate of DOAC usage in Japan is higher than the typical global average (31%–48%), 20 , 21 , 22 and certainly, in this study of patients with both HCM and NVAF, we observed a larger proportion of DOAC‐treated patients than those treated with warfarin, possibly reflecting the impact of increased DOAC availability across Japan. 20 , 21 , 22 Interestingly, previous studies investigating all patients with NVAF have shown that among those assessed from 2012 to 2013 to those assessed from 2016 to 2017, a significant increase in DOAC treatment was observed for Japanese patients alongside a concurrent decrease in warfarin usage. 22
Several demographic trends were observed in this study. A higher proportion of males was observed in both the DOAC‐ and warfarin‐treated groups. These results are consistent with previous studies showing that within the Japanese population, men are more often diagnosed with AF and account for the majority of HCM cases identified within the Japanese National Registry of Clinical Personal Records Database. 23 , 24 The mean age of patients in the DOAC (74.8 years) and warfarin (75.3 years) groups in the current study was higher than that reported previously (Spain 25 : mean 61–62 years; US 15 : median 67 years; and Korea 16 : mean 67–71 years). Interestingly, as observed in other studies of patients with HCM, 15 , 16 , 25 most patients in the present study had multiple comorbidities. However, the proportions of those with hypertension (73.9%–75.4%) and diabetes mellitus (46.5%–47.5%) in both cohorts were greater than those reported in studies from Spain (48%–57% and 16%–21%, respectively). 25 This difference may reflect the older age of the population in the present study, as hypertension tends to increase with age. The incidence of hypertension observed in the current study was comparable with that seen in patients with AF and without HCM in Japan overall, although diabetes was less frequent (21%–22%). 26 , 27
Patients with HCM and NVAF treated with DOACs showed comparable bleeding rates and lower thromboembolic rates compared with those treated with warfarin. Previous cohorts of Japanese patients with AF but without HCM have also shown similar bleeding rates, although these rates were lower for patients treated with DOACs. 27 Based on landmark clinical trials, the latest guidelines recommend DOACs rather than warfarin for the treatment of most NVAF cases, owing to their equivalent efficacy, superior safety profile and lower incidence of haemorrhage. 12 , 19 , 28 , 29 , 30 However, although not formally excluded from these DOAC trials, the number of patients with HCM within these studies was unknown, and thus, the impact of concurrent HCM and NVAF on treatment practices is unclear. Data from the present study suggest that patients with HCM and NVAF can be safely and effectively treated with DOACs. One explanation for the lower incidence of stroke/SE among patients treated with DOACs in this study could be that real‐world management of warfarin may be less strict compared with that observed within clinical trials. The incidence rates per 100 person‐years of stroke/SE in the current study (DOAC, 2.30; warfarin, 3.27) were higher than those observed in patients without a background of HCM. In a retrospective chart review‐OAC study, for example, the incidence rate of stroke/SE was 1.14 and 1.73 per 100‐person years for patients treated with DOACs and warfarin, respectively. 27 The STroke prevention ANticoagulant Drug Apixaban Real‐world Data (STANDARD) study showed that for patients treated with DOACs, only 1.0% experienced a stroke/SE/TIA per year. 31 Results from the current study may, therefore, suggest that HCM is a strong risk factor for or a modifier of thromboembolism in patients with NVAF. This is consistent with previous reports indicating that HCM is a substantial and strong risk factor for thromboembolism. 32 , 33 In addition, CKD was identified as a risk factor for both major bleeding and stroke; however, renal dysfunction is a known risk factor for both in the general AF population 34 , 35 and was shown to be the same in the HCM‐only population. Our study also demonstrated that previous stroke augmented stroke/SE event risk by approximately three‐fold in patients with both HCM and NVAF. Similarly, among patients without an HCM background, prior stroke has also been shown to increase the risk of stroke by approximately three‐fold. 26 This is supported by a recent study of patients with HCM and AF from the Korean National Health Insurance database, in which 45.8%–48.4% of patients had experienced a prior stroke/SE after PS matching, indicating that the Korean population assessed was a high‐risk population at baseline. 16
This study has several strengths. These observational data provide important insights into real‐world clinical outcomes associated with DOAC use in patients with HCM and NVAF, a group not well studied in previously published or ongoing clinical trials. The MDV database includes a broad range of patients and hospitals in Japan (approximately 40 million patients in over 460 DPC hospitals, representing approximately 26% of all DPC hospitals in Japan). 36 The study population included a large sample of patients diagnosed with both HCM and AF who were treated in a routine clinical practice setting.
The study also has a few limitations. First, as an observational study, the ability to draw causal inferences was limited owing to residual unmeasured confounding. Second, this study relied on billing codes for patient characteristics and outcome adjudication. Consequently, clinical characteristics, such as mitral valve dysfunction, left atrial enlargement, left ventricular dysfunction and other factors that may predispose patients to cardioembolism, were not recorded. Information on family history of HCM and sudden death was unavailable. Third, certain variables, such as body weight, left atrial dimension, persistent or permanent AF and haemoglobin levels, were not considered for PS matching; thus, it is uncertain whether these characteristics were fully balanced between the groups. Fourth, the incidence of bleeding or stroke/SE events may have been underestimated if patients had decided to visit a different DPC hospital or general practitioner. Fifth, no data were available for time in the therapeutic range for the warfarin group owing to limitations in the health claims database. Poor time in therapeutic range may have affected the favourable mortality outcomes observed in the DOAC group. Sixth, the MDV database is not a closed system; thus, services received outside MDV hospitals are not captured, such as some hospitalisations, post‐discharge visits and outpatient visits. Last, echocardiographic data were unavailable; therefore, the association between cardiac function and stroke events could not be assessed.
The findings from this retrospective observational cohort study show that patients with HCM and NVAF in a Japanese cohort treated with DOACs have similar bleeding risks as those treated with warfarin and a lower risk of stroke/SE. Previous stroke was shown to augment stroke risk by approximately three‐fold. This study suggests that patients diagnosed with both HCM and NVAF can be safely and effectively treated with DOACs.
Conflict of interest statement
R. C., N. E., B. C. T. and Y. M. are employees of Bristol Myers Squibb. H. K. has received honoraria from AstraZeneca, Daiichi‐Sankyo, Novartis, Ohtsuka, Pfizer and Takeda. T. K. has received honoraria from Bristol Myers Squibb, Pfizer, Sumitomo Pharma, Takeda and AstraZeneca.
Funding
This study was funded and conducted by Bristol Myers Squibb K.K.
Supporting information
Table S1. Definition of diseases or conditions by ICD‐10 diagnosis codes/disease codes/procedure codes.
Table S2. Covariate balance before and after nearest‐neighbour matching for the DOAC and warfarin groups.
Acknowledgements
Writing, editorial support and formatting assistance were provided by Rebecca Watkin, PhD, of Cactus Life Sciences (part of Cactus Communications), who was contracted and compensated by Bristol Myers Squibb K.K. for these services. Bristol Myers Squibb K.K. was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.
Kitaoka, H. , Carroll, R. , Eugene, N. , Teixeira, B. C. , Matsuo, Y. , and Kubo, T. (2025) Oral anticoagulation in patients with hypertrophic cardiomyopathy and non‐valvular atrial fibrillation in Japan. ESC Heart Failure, 12: 326–337. 10.1002/ehf2.15039.
References
- 1. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124:2761‐2796. doi: 10.1161/CIR.0b013e318223e230 [DOI] [PubMed] [Google Scholar]
- 2. Authors/Task Force Members , Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, et al. 2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the task force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J 2014;35:2733‐2779. doi: 10.1093/eurheartj/ehu284 [DOI] [PubMed] [Google Scholar]
- 3. Kitaoka H, Tsutsui H, Kubo T, Ide T, Chikamori T, Fukuda K, et al. JCS/JHFS 2018 guideline on the diagnosis and treatment of cardiomyopathies. Circ J 2021;85:1590‐1689. doi: 10.1253/circj.CJ-20-0910 [DOI] [PubMed] [Google Scholar]
- 4. Maron BJ, Gardin JM, Flack JM, Gidding SS, Kurosaki TT, Bild DE. Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA study. Coronary Artery Risk Development in (Young) Adults. Circulation 1995;92:785‐789. doi: 10.1161/01.cir.92.4.785 [DOI] [PubMed] [Google Scholar]
- 5. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol 2015;65:1249‐1254. doi: 10.1016/j.jacc.2015.01.019 [DOI] [PubMed] [Google Scholar]
- 6. Maron BJ. Clinical course and management of hypertrophic cardiomyopathy. N Engl J Med 2018;379:655‐668. doi: 10.1056/NEJMra1710575 [DOI] [PubMed] [Google Scholar]
- 7. Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation 2018;138:1387‐1398. doi: 10.1161/CIRCULATIONAHA.117.033200 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Maron BJ, Olivotto I, Bellone P, Conte MR, Cecchi F, Flygenring BP, et al. Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39:301‐307. doi: 10.1016/s0735-1097(01)01727-2 [DOI] [PubMed] [Google Scholar]
- 9. Siontis KC, Geske JB, Ong K, Nishimura RA, Ommen SR, Gersh BJ. Atrial fibrillation in hypertrophic cardiomyopathy: prevalence, clinical correlations, and mortality in a large high‐risk population. J Am Heart Assoc 2014;3:e001002. doi: 10.1161/JAHA.114.001002 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Kubo T, Baba Y, Ochi Y, Hirota T, Yamasaki N, Kawai K, et al. Clinical significance of new‐onset atrial fibrillation in patients with hypertrophic cardiomyopathy. ESC Heart Fail 2021;8:5022‐5030. doi: 10.1002/ehf2.13563 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Terasaka N, Spanopoulos D, Miyagoshi H, Kubo T, Kitaoka H. Estimating the prevalence, clinical characteristics, and treatment patterns of hypertrophic cardiomyopathy in Japan: a nationwide medical claims database study. J Cardiol 2023;81:316‐322. doi: 10.1016/j.jjcc.2022.09.015 [DOI] [PubMed] [Google Scholar]
- 12. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales‐Villa R, Basso C, et al. 2023 ESC guidelines for the management of cardiomyopathies. G Ital Cardiol (Rome) 2023;24:1e‐127e. doi: 10.1714/4127.41209 [DOI] [PubMed] [Google Scholar]
- 13. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström‐Lundqvist C, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio‐Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021;42:373‐498. doi: 10.1093/eurheartj/ehaa612 Erratum in: Eur Heart J. 2021 Feb 1;42(5):507. Erratum in: Eur Heart J. 2021 Feb 1;42(5):546–547. Erratum in: Eur Heart J. 2021 Oct 21;42(40):4194. PMID: 32860505 [DOI] [PubMed] [Google Scholar]
- 14. Ono K, Iwasaki YK, Akao M, Ikeda T, Ishii K, Inden Y, et al. JCS/JHRS 2020 guideline on pharmacotherapy of cardiac arrhythmias. Circ J 2022;86:1790‐1924. doi: 10.1253/circj.CJ-20-1212 [DOI] [PubMed] [Google Scholar]
- 15. Noseworthy PA, Yao X, Shah ND, Gersh BJ. Stroke and bleeding risks in NOAC‐ and warfarin‐treated patients with hypertrophic cardiomyopathy and atrial fibrillation. J Am Coll Cardiol 2016;67:3020‐3021. doi: 10.1016/j.jacc.2016.04.026 PMID: 27339501 [DOI] [PubMed] [Google Scholar]
- 16. Jung H, Yang PS, Jang E, Yu HT, Kim TH, Uhm JS, et al. Effectiveness and safety of non‐vitamin K antagonist oral anticoagulants in patients with atrial fibrillation with hypertrophic cardiomyopathy: a nationwide cohort study. Chest 2019;155:354‐363. doi: 10.1016/j.chest.2018.11.009 [DOI] [PubMed] [Google Scholar]
- 17. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis . Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non‐surgical patients. J Thromb Haemost 2005;3:692‐694. doi: 10.1111/j.1538-7836.2005.01204.x [DOI] [PubMed] [Google Scholar]
- 18. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee on Control of Anticoagulation . Definition of clinically relevant non‐major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non‐surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015;13:2119‐2126. doi: 10.1111/jth.13140 [DOI] [PubMed] [Google Scholar]
- 19. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981‐992. doi: 10.1056/NEJMoa1107039 [DOI] [PubMed] [Google Scholar]
- 20. Huisman MV, Rothman KJ, Paquette M, Teutsch C, Diener HC, Dubner SJ, et al. Antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation: the GLORIA‐AF registry, phase II. Am J Med 2015;128:1306‐1313.e1. doi: 10.1016/j.amjmed.2015.07.013 [DOI] [PubMed] [Google Scholar]
- 21. Başaran Ö, Beton O, Doğan V, Tekinalp M, Aykan AÇ, Kalaycıoğlu E, et al. ReAl‐life Multicenter Survey Evaluating Stroke prevention strategies in non‐valvular atrial fibrillation (RAMSES study). Anatol J Cardiol 2016;16:734‐741. doi: 10.14744/AnatolJCardiol.2016.6752 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Ono T, Ikemura N, Kimura T, Ueda I, Tanaka H, Tokuda H, et al. Contemporary trend of reduced‐dose non‐vitamin K anticoagulants in Japanese patients with atrial fibrillation: a cross‐sectional analysis of a multicenter outpatient registry. J Cardiol 2019;73:14‐21. doi: 10.1016/j.jjcc.2018.09.003 [DOI] [PubMed] [Google Scholar]
- 23. Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, et al. Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. Int J Cardiol 2009;137:102‐107. doi: 10.1016/j.ijcard.2008.06.029 [DOI] [PubMed] [Google Scholar]
- 24. Enzan N, Matsushima S, Ide T, Kaku H, Tohyama T, Funakoshi K, et al. Clinical characteristics and contemporary management of patients with cardiomyopathies in Japan—report from a National Registry of Clinical Personal Records. Circ Rep 2021;3:142‐152. doi: 10.1253/circrep.CR-21-0001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Dominguez F, Climent V, Zorio E, Ripoll‐Vera T, Salazar‐Mendiguchía J, García‐Pinilla JM, et al. Direct oral anticoagulants in patients with hypertrophic cardiomyopathy and atrial fibrillation. Int J Cardiol 2017;248:232‐238. doi: 10.1016/j.ijcard.2017.08.010 [DOI] [PubMed] [Google Scholar]
- 26. Okumura K, Tomita H, Nakai M, Kodani E, Akao M, Suzuki S, et al. Risk factors associated with ischemic stroke in Japanese patients with nonvalvular atrial fibrillation. JAMA Netw Open 2020;3:e202881. doi: 10.1001/jamanetworkopen.2020.2881 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Koretsune Y, Hoshino H, Matsuo Y, Ibuki T, Morimoto T. Comparative safety and effectiveness of apixaban vs. warfarin in oral anticoagulant‐naïve Japanese patients with non‐valvular atrial fibrillation—a retrospective chart review study. Circ J 2022;86:213. doi: 10.1253/circj.CJ-21-0682 [DOI] [PubMed] [Google Scholar]
- 28. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093‐2104. doi: 10.1056/NEJMoa1310907 [DOI] [PubMed] [Google Scholar]
- 29. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883‐891. doi: 10.1056/NEJMoa1009638 [DOI] [PubMed] [Google Scholar]
- 30. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139‐1151. doi: 10.1056/NEJMoa0905561 [DOI] [PubMed] [Google Scholar]
- 31. Inoue H, Umeyama M, Yamada T, Hashimoto H, Komoto A, Yasaka M. Safety and effectiveness of apixaban in Japanese patients with nonvalvular atrial fibrillation in clinical practice: a regulatory postmarketing surveillance, the STANDARD study. J Arrhythm 2019;35:506‐514. doi: 10.1002/joa3.12184 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation 2001;104:2517‐2524. doi: 10.1161/hc4601.097997 [DOI] [PubMed] [Google Scholar]
- 33. Guttmann OP, Rahman MS, O'Mahony C, Anastasakis A, Elliott PM. Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review. Heart 2014;100:465‐472. doi: 10.1136/heartjnl-2013-304276 [DOI] [PubMed] [Google Scholar]
- 34. Abe M, Ogawa H, Ishii M, Masunaga N, Esato M, Chun Y‐H, et al. Relation of stroke and major bleeding to creatinine clearance in patients with atrial fibrillation (from the Fushimi AF registry). Am J Cardiol 2017;119:1229‐1237. doi: 10.1016/j.amjcard.2017.01.005 [DOI] [PubMed] [Google Scholar]
- 35. Kodani E, Atarashi H, Inoue H, Okumura K, Yamashita T, Origasa H, et al. Impact of creatinine clearance on outcomes in patients with non‐valvular atrial fibrillation: a subanalysis of the J‐RHYTHM registry. Eur Heart J Qual Care Clin Outcomes 2018;4:59‐68. doi: 10.1093/ehjqcco/qcx032 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Medical Data Vision Co., Ltd . About MDV database. https://en.mdv.co.jp/ebm/about‐mdv‐database. Accessed 4 December 2022
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Definition of diseases or conditions by ICD‐10 diagnosis codes/disease codes/procedure codes.
Table S2. Covariate balance before and after nearest‐neighbour matching for the DOAC and warfarin groups.